Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTX1CTFB)

• DOT Name: HLA class I histocompatibility antigen, alpha chain E (HLA-E)
• Synonyms: MHC class I antigen E
• Gene Name: HLA-E
• Related Disease:
  Behcet disease
  Acute graft versus host disease
  Adult glioblastoma
  Ankylosing spondylitis
  Autoimmune disease
  Bipolar disorder
  Cervical cancer
  Cervical carcinoma
  Chronic graft versus host disease
  Clear cell renal carcinoma
  Colon cancer
  Colon carcinoma
  Cytomegalovirus infection
  Epithelial ovarian cancer
  Esophageal squamous cell carcinoma
  Glioblastoma multiforme
  Glioma
  Graft-versus-host disease
  Hematologic disease
  Hepatitis B virus infection
  Hepatitis C virus infection
  Hepatocellular carcinoma
  Latent tuberculosis infection
  Metastatic malignant neoplasm
  Myelodysplastic syndrome
  Myocardial ischemia
  Nasopharyngeal carcinoma
  Neoplasm
  Nephropathy
  Ovarian cancer
  Ovarian neoplasm
  Plasma cell myeloma
  Pneumonia
  Pneumonitis
  Psoriasis
  Psychotic disorder
  Renal cell carcinoma
  Rheumatoid arthritis
  Tuberculosis
  Carcinoma
  HIV infectious disease
  Melanoma
  Type-1 diabetes
  Acute leukaemia
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Coronary heart disease
  Neuroblastoma
• UniProt ID: HLAE_HUMAN
• PDB ID: 1KPR; 1KTL; 1MHE; 2ESV; 3AM8; 3BZE; 3BZF; 3CDG; 3CII; 5W1V; 5W1W; 6GGM; 6GH1; 6GH4; 6GHN; 6GL1; 6ZKW; 6ZKX; 6ZKY; 6ZKZ; 7BH8; 7NDQ; 7NDT; 7NDU; 7P49; 7P4B
• Pfam ID: PF07654 ; PF00129 ; PF06623
• Sequence:
  MVDGTLLLLLSEALALTQTWAGSHSLKYFHTSVSRPGRGEPRFISVGYVDDTQFVRFDND
  AASPRMVPRAPWMEQEGSEYWDRETRSARDTAQIFRVNLRTLRGYYNQSEAGSHTLQWMH
  GCELGPDGRFLRGYEQFAYDGKDYLTLNEDLRSWTAVDTAAQISEQKSNDASEAEHQRAY
  LEDTCVEWLHKYLEKGKETLLHLEPPKTHVTHHPISDHEATLRCWALGFYPAEITLTWQQ
  DGEGHTQDTELVETRPAGDGTFQKWAAVVVPSGEEQRYTCHVQHEGLPEPVTLRWKPASQ
  PTIPIVGIIAGLVLLGSVVSGAVVAAVIWRKKSSGGKGGSYSKAEWSDSAQGSESHSL
• Function: Non-classical major histocompatibility class Ib molecule involved in immune self-nonself discrimination. In complex with B2M/beta-2-microglobulin binds nonamer self-peptides derived from the signal sequence of classical MHC class Ia molecules (VL9 peptides - VMAPRT[V/L][L/V/I/F]L). Peptide-bound HLA-E-B2M heterotrimeric complex primarily functions as a ligand for natural killer (NK) cell inhibitory receptor KLRD1-KLRC1, enabling NK cells to monitor the expression of other MHC class I molecules in healthy cells and to tolerate self. Upon cellular stress, preferentially binds signal sequence-derived peptides from stress-induced chaperones and is no longer recognized by NK cell inhibitory receptor KLRD1-KLRC1, resulting in impaired protection from NK cells. Binds signal sequence-derived peptides from non-classical MHC class Ib HLA-G molecules and acts as a ligand for NK cell activating receptor KLRD1-KLRC2, likely playing a role in the generation and effector functions of adaptive NK cells and in maternal-fetal tolerance during pregnancy. Besides self-peptides, can also bind and present pathogen-derived peptides conformationally similar to VL9 peptides to alpha-beta T cell receptor (TCR) on unconventional CD8-positive cytotoxic T cells, ultimately triggering antimicrobial immune response. Presents HIV gag peptides (immunodominant KAFSPEVIPMF and subdominant KALGPAATL epitopes) predominantly to CD8-positive T cell clones expressing a TRAV17-containing TCR, triggering HLA-E-restricted T cell responses. Presents mycobacterial peptides to HLA-E-restricted CD8-positive T cells eliciting both cytotoxic and immunoregulatory functions ; (Microbial infection) Viruses like human cytomegalovirus have evolved an escape mechanism whereby virus-induced down-regulation of host MHC class I molecules is coupled to the binding of viral peptides to HLA-E, restoring HLA-E expression and inducing HLA-E-dependent NK cell immune tolerance to infected cells; (Microbial infection) May bind HIV-1 gag/Capsid protein p24-derived peptide (AISPRTLNA) on infected cells and may inhibit NK cell cytotoxicity, a mechanism that allows HIV-1 to escape immune recognition; (Microbial infection) Upon SARS-CoV-2 infection, may contribute to functional exhaustion of cytotoxic NK cells and CD8-positive T cells. Binds SARS-CoV-2 S/Spike protein S1-derived peptide (LQPRTFLL) expressed on the surface of lung epithelial cells, inducing NK cell exhaustion and dampening of antiviral immune surveillance.
• Tissue Specificity: Expressed in secretory endometrial cells during pregnancy (at protein level). The expression in nonlymphoid tissues is restricted to endothelial cells from all types of vessels, including arteries, veins, capillaries, and lymphatics (at protein level). In lymphoid organs, it is mainly expressed in endothelial venules, B and T cells, monocytes, macrophages, NK cells and megakaryocytes (at protein level).
• KEGG Pathway:
  Endocytosis (hsa04144)
  Phagosome (hsa04145)
  Cellular senescence (hsa04218)
  Cell adhesion molecules (hsa04514)
  Antigen processing and presentation (hsa04612)
  .tural killer cell mediated cytotoxicity (hsa04650)
  Type I diabetes mellitus (hsa04940)
  Human cytomegalovirus infection (hsa05163)
  Human papillomavirus infection (hsa05165)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Herpes simplex virus 1 infection (hsa05168)
  Epstein-Barr virus infection (hsa05169)
  Human immunodeficiency virus 1 infection (hsa05170)
  Viral carcinogenesis (hsa05203)
  Autoimmune thyroid disease (hsa05320)
  Allograft rejection (hsa05330)
  Graft-versus-host disease (hsa05332)
  Viral myocarditis (hsa05416)
• Reactome Pathway:
  Endosomal/Vacuolar pathway (R-HSA-1236977)
  Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell (R-HSA-198933)
  DAP12 interactions (R-HSA-2172127)
  DAP12 signaling (R-HSA-2424491)
  Interferon gamma signaling (R-HSA-877300)
  Interferon alpha/beta signaling (R-HSA-909733)
  SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)
  Antigen Presentation (R-HSA-983170)
  ER-Phagosome pathway (R-HSA-1236974)

Molecular Interaction Atlas (MIA) of This DOT

49 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Behcet disease	DISSYMBS	Definitive	Genetic Variation	[1]
Acute graft versus host disease	DIS8KLVM	Strong	Genetic Variation	[2]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[3]
Ankylosing spondylitis	DISRC6IR	Strong	Genetic Variation	[4]
Autoimmune disease	DISORMTM	Strong	Biomarker	[5]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[6]
Cervical cancer	DISFSHPF	Strong	Biomarker	[7]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[7]
Chronic graft versus host disease	DIS1MM9J	Strong	Genetic Variation	[2]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[8]
Colon cancer	DISVC52G	Strong	Altered Expression	[9]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[9]
Cytomegalovirus infection	DISCEMGC	Strong	Altered Expression	[10]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[11]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[12]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[3]
Glioma	DIS5RPEH	Strong	Altered Expression	[13]
Graft-versus-host disease	DIS0QADF	Strong	Genetic Variation	[2]
Hematologic disease	DIS9XD9A	Strong	Biomarker	[14]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[15]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[16]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[17]
Latent tuberculosis infection	DIS6R1EH	Strong	Biomarker	[18]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[19]
Myelodysplastic syndrome	DISYHNUI	Strong	Altered Expression	[20]
Myocardial ischemia	DISFTVXF	Strong	Biomarker	[21]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Genetic Variation	[22]
Neoplasm	DISZKGEW	Strong	Biomarker	[23]
Nephropathy	DISXWP4P	Strong	Genetic Variation	[24]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[11]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[25]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[23]
Pneumonia	DIS8EF3M	Strong	Altered Expression	[26]
Pneumonitis	DIS88E0K	Strong	Altered Expression	[26]
Psoriasis	DIS59VMN	Strong	Biomarker	[27]
Psychotic disorder	DIS4UQOT	Strong	Biomarker	[28]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[8]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[29]
Tuberculosis	DIS2YIMD	Strong	Biomarker	[30]
Carcinoma	DISH9F1N	moderate	Biomarker	[31]
HIV infectious disease	DISO97HC	moderate	Biomarker	[32]
Melanoma	DIS1RRCY	moderate	Altered Expression	[33]
Type-1 diabetes	DIS7HLUB	moderate	Genetic Variation	[34]
Acute leukaemia	DISDQFDI	Limited	Altered Expression	[35]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[36]
Breast cancer	DIS7DPX1	Limited	Genetic Variation	[37]
Breast carcinoma	DIS2UE88	Limited	Genetic Variation	[37]
Coronary heart disease	DIS5OIP1	Limited	Genetic Variation	[38]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[39]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Carbamazepine	DMZOLBI	Approved	HLA class I histocompatibility antigen, alpha chain E (HLA-E) affects the response to substance of Carbamazepine.	[67]

40 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of HLA class I histocompatibility antigen, alpha chain E (HLA-E).	[40]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of HLA class I histocompatibility antigen, alpha chain E (HLA-E).	[41]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of HLA class I histocompatibility antigen, alpha chain E (HLA-E).	[42]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of HLA class I histocompatibility antigen, alpha chain E (HLA-E).	[43]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of HLA class I histocompatibility antigen, alpha chain E (HLA-E).	[44]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of HLA class I histocompatibility antigen, alpha chain E (HLA-E).	[45]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of HLA class I histocompatibility antigen, alpha chain E (HLA-E).	[46]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of HLA class I histocompatibility antigen, alpha chain E (HLA-E).	[47]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of HLA class I histocompatibility antigen, alpha chain E (HLA-E).	[48]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of HLA class I histocompatibility antigen, alpha chain E (HLA-E).	[49]
Selenium	DM25CGV	Approved	Selenium increases the expression of HLA class I histocompatibility antigen, alpha chain E (HLA-E).	[50]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of HLA class I histocompatibility antigen, alpha chain E (HLA-E).	[51]
Menadione	DMSJDTY	Approved	Menadione affects the expression of HLA class I histocompatibility antigen, alpha chain E (HLA-E).	[52]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of HLA class I histocompatibility antigen, alpha chain E (HLA-E).	[53]
Etoposide	DMNH3PG	Approved	Etoposide affects the expression of HLA class I histocompatibility antigen, alpha chain E (HLA-E).	[54]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of HLA class I histocompatibility antigen, alpha chain E (HLA-E).	[55]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of HLA class I histocompatibility antigen, alpha chain E (HLA-E).	[56]
Malathion	DMXZ84M	Approved	Malathion decreases the expression of HLA class I histocompatibility antigen, alpha chain E (HLA-E).	[57]
Simvastatin	DM30SGU	Approved	Simvastatin affects the expression of HLA class I histocompatibility antigen, alpha chain E (HLA-E).	[54]
Thalidomide	DM70BU5	Approved	Thalidomide affects the expression of HLA class I histocompatibility antigen, alpha chain E (HLA-E).	[54]
Sodium phenylbutyrate	DMXLBCQ	Approved	Sodium phenylbutyrate increases the expression of HLA class I histocompatibility antigen, alpha chain E (HLA-E).	[58]
Ciprofloxacin XR	DM2NLS9	Approved	Ciprofloxacin XR affects the expression of HLA class I histocompatibility antigen, alpha chain E (HLA-E).	[54]
Famotidine	DMRL3AB	Approved	Famotidine affects the expression of HLA class I histocompatibility antigen, alpha chain E (HLA-E).	[54]
Ofloxacin	DM0VQN3	Approved	Ofloxacin affects the expression of HLA class I histocompatibility antigen, alpha chain E (HLA-E).	[54]
Hydrochlorothiazide	DMUSZHD	Approved	Hydrochlorothiazide affects the expression of HLA class I histocompatibility antigen, alpha chain E (HLA-E).	[54]
Ketorolac	DMI4EL5	Approved	Ketorolac affects the expression of HLA class I histocompatibility antigen, alpha chain E (HLA-E).	[54]
Clindamycin	DM15HL8	Approved	Clindamycin affects the expression of HLA class I histocompatibility antigen, alpha chain E (HLA-E).	[54]
Tolmetin	DMWUIJE	Approved	Tolmetin affects the expression of HLA class I histocompatibility antigen, alpha chain E (HLA-E).	[54]
Cefuroxime	DMSIMD8	Approved	Cefuroxime affects the expression of HLA class I histocompatibility antigen, alpha chain E (HLA-E).	[54]
Lincomycin	DMVTHER	Approved	Lincomycin affects the expression of HLA class I histocompatibility antigen, alpha chain E (HLA-E).	[54]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of HLA class I histocompatibility antigen, alpha chain E (HLA-E).	[59]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of HLA class I histocompatibility antigen, alpha chain E (HLA-E).	[60]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of HLA class I histocompatibility antigen, alpha chain E (HLA-E).	[42]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of HLA class I histocompatibility antigen, alpha chain E (HLA-E).	[50]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of HLA class I histocompatibility antigen, alpha chain E (HLA-E).	[61]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of HLA class I histocompatibility antigen, alpha chain E (HLA-E).	[62]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of HLA class I histocompatibility antigen, alpha chain E (HLA-E).	[63]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of HLA class I histocompatibility antigen, alpha chain E (HLA-E).	[64]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine increases the expression of HLA class I histocompatibility antigen, alpha chain E (HLA-E).	[65]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN affects the expression of HLA class I histocompatibility antigen, alpha chain E (HLA-E).	[66]

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